DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Notice of Pre-AIA or AIA Status
This action is written in response to applicant’s correspondence received 21 October 2025. Claims 1, 4-5, 23, 25, 27, 29, 31, 33-34, 40, 42-43, 50, and 80-88 are currently pending. Claims 29 and 31 are withdrawn from examination. Accordingly, claims 1, 4-5, 23, 25, 27, 33-34, 40, 42-43, 50, and 80-88 are examined herein. The restriction requirement mailed 22 November 2024 is still deemed proper. Applicant's elected Group I alongside SEQ ID NOs: 85, 191, 1064, 1070, 1173, and a Gln455 Lys mutation without traverse in the reply filed 2 February 2025.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4-5, 42-43, 50, and 84-85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024) in view of Wieben (WO 2013/101711 A1, cited in the IDS filed 30 May 2024).
Regarding claims 1 and 5, Zhang teaches the use of a CRISPR-Cas system that comprises guide sequences that directs a nuclease to a target sequence of interest ([0011]). Zhang teaches that the CRISPR system can be utilized alongside a guide RNA to treat a condition caused by a defect in a target sequence ([0035]). Zhang teaches that the CRISPR system may be present within a dosage comprising a pharmaceutically-acceptable carrier (i.e., in a pharmaceutical formulation) ([0191]). Zhang teaches that genomic DNA encoding trinucleotide repeat disorders are preferred conditions to be treated ([0224]), and specifically mentions that FECD (i.e., Fuchs’ endothelial corneal dystrophy) is an ocular disease that can be treated via the utilization of a CRISPR system (Page 41, Table B). Zhang teaches that the guide RNA sequences can be 20 nucleotides in length ([0296]). Zhang teaches that guide RNAs are able to be designed in order to target and treat a multitude of different diseases, including Glaucoma, Amyloidosis, and Huntington’s Disease ([0572]-[0577]). Zhang teaches the use of an S.pyogenes Cas9 guide RNA that can target a sequence that is directly upstream of a 5’-NGG PAM sequence ([0087]).
Zhang does not teach or suggest that the guide sequence directs a nuclease to a target sequence selected from SEQ ID NO: 85 in a tri-nucleotide repeat in a transcription factor four gene (Claims 1 and 84). Zhang does not teach or suggest that the guide sequence is 100% identical to SEQ ID NO: 1173 (Claims 5 and 85).
However, one of ordinary skill in the art would have considered the teachings of Wieben as both references are common fields of endeavor pertaining to the study of Fuchs’ endothelial corneal dystrophy.
Wieben is directed towards assessing the likelihood of developing Fuchs’ Corneal Dystrophy and teaches kits that can be used to assess a mammal for the presence or absence of an expanded TGC repeat within intron 3 of TCF 4 nucleic acid in order to determine if a subject has FECD (Pages 3, 10). Wieben, although directed towards primer sequences, teaches that the claimed SEQ ID NOs 85 and 1173 are complementary sequences present in the listed sequence of intron 3 of TCF4 (Pages 8-9, see SEQ ID NO: 1 in previously attached sequence alignment). Wieben further teaches that primers can be designed to hybridize to the intron (Page 10, Lines 13-18).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to try to modify the guide Sequence of Zhang such that it targeted a sequence having 100% identity to the claimed SEQ ID NO: 85 with a guide sequence having 100% identity to the claimed SEQ ID NO: 1173, as described in Wieben. A person of ordinary skill in the art would have recognized that Zhang identified a need in the art to target genes associated with FECD by targeting an S. pyogenes CRISPR system to a defect in the target sequence that is upstream of a NGG PAM sequence while Wieben teaches that the claimed SEQ ID NOs: 85 and 1173 were known complementary sequences in a transcription factor four gene that comprised a trinucleotide repeat associated with FECD and were directly upstream of an AGG sequence (i.e., an NGG PAM sequence). A person of ordinary skill in the art would have recognized that there are a finite number of guide RNAs that can be designed in order to target the TCF4 gene that is upstream of an NGG PAM, as described in Wieben. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued with a reasonable expectation of success because Zhang teaches that guide RNAs are able to be designed in order to target and treat a multitude of different diseases.
Regarding claim 4, Zhang teaches that the guide RNA comprises a tracrRNA (i.e., a trRNA) and a guide sequence (i.e., the guide RNA of Zhang is a single guide RNA comprising a trRNA) ([0271]).
Regarding claims 42-43, Zhang teaches that a CRISPR-Cas nuclease may be delivered to the cell in the form of mRNA ([0020]).
Regarding claim 50, Zhang teaches that the system comprises administering a therapeutically effective amount of a CRISPR-Cas gene therapy particle and a pharmaceutically acceptable carrier to the cells of a subject ([191]).
Claim(s) 23, 25, 33, 81-82, and 86-88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024), Courtney (Int J Ophthalmol Eye Res. S 2 (2015): 7-18), and Mammalian Genome Collection (i.e., MGC) (Proceedings of the National Academy of Sciences 99.26 (2002): 16899-16903).
Regarding claims 23, 25 and 87-88, Zhang teaches the use of a CRISPR-Cas system that comprises guide sequences that directs a nuclease to a target sequence of interest ([0011]). Zhang teaches that the CRISPR system can be utilized alongside a guide RNA to treat a condition caused by a defect in a target sequence ([0035]). Zhang teaches that the CRISPR system may be present within a dosage comprising a pharmaceutically-acceptable carrier (i.e., in a pharmaceutical formulation) ([0191]). Zhang teaches that genomic DNA encoding trinucleotide repeat disorders are preferred conditions to be treated ([0224]), and specifically mentions that FECD (i.e., Fuchs’ endothelial corneal dystrophy) is an ocular disease that can be treated (Page 41, Table B). Zhang teaches that the guide RNA sequences can be 20 nucleotides in length ([0296]). Zhang teaches that guide RNAs are able to be designed in order to target and treat a multitude of different diseases, including Glaucoma, Amyloidosis, and Huntington’s Disease ([0572]-[0577]).
Zhang does not teach or suggest that the guide sequence directs a nuclease to a target sequence selected from SEQ ID NO: 191 in an alpha 2 subunit of the collagen type VIII gene (Claims 23, 25, 86-88).
Courtney is drawn to a review paper concerned with the use of CRISPR/Cas9 to treat corneal disorders (Abstract). Courtney teaches that Col8A2 is a gene known to be associated with Fuchs’ endothelial corneal dystrophy (pg. 8; see Table 1). Courtney teaches that CRISPR systems can be utilized to treat ocular diseases via the use of guide RNA molecules comprising uracil that can be designed to target and edit a gene associated with corneal disorders (pg. 11).
MGC is drawn to a study concerned with the generation of full-length human and mouse cDNA sequences (Abstract). MGC teaches the use of a Col8A2 gene that is 836 base pairs long and has a region comprising a complementary base sequencing having 100% sequence identity to the claimed SEQ ID NO: 191 (see previously attached sequence alignment).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to try to modify the guide RNA of Zhang such that it that comprised 100% sequence identity to the claimed SEQ ID NO: 191, as described by Courtney and MGC. A person of ordinary skill in the art would have recognized that Courtney identified a need in the art to target Col8A2 as it is associated with FECD. A person of ordinary skill in the art would have recognized that there are a finite number of guide RNAs that can be designed in order to target the Col8A2 gene, as described by Zhang. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued with a reasonable expectation of success because Zhang teaches that guide RNAs are able to be designed in order to target and treat different ocular diseases.
Regarding claim 33, Zhang teaches that the guide RNA comprises a tracrRNA (i.e., a trRNA) and a guide sequence (i.e., the guide RNA of Zhang is a single guide RNA comprising a trRNA) ([0271]).
Regarding claims 81-82, Zhang teaches that a CRISPR-Cas nuclease may be delivered to the cell in the form of mRNA ([0020]).
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024), Courtney (Int J Ophthalmol Eye Res. S 2 (2015): 7-18), and Mammalian Genome Collection (i.e., MGC) (Proceedings of the National Academy of Sciences 99.26 (2002): 16899-16903) as applied to claims 23, 25, 33, 81-82, and 86-88 above, and further in view of Muragaki (Journal of Biological Chemistry 266.12 (1991): 7721-7727).
Regarding claim 27, Zhang in view of Courtney and MGC renders obvious claims 23, 25, 33, 81-82, and 86-88 as described above.
Zhang in view of Courtney and MGC does not teach or suggest that the guide RNA is complementary or identical to the claimed SEQ ID NO: 1064 (Claim 23).
However, one of ordinary skill in the art would have considered the teachings of Muragaki as both references are common fields of endeavor pertaining to the treatment of genes associated Fuchs’ endothelial corneal dystrophy via CRISPR systems.
Muragaki is drawn to a study concerned with an alpha 2(VIII) collagen gene (Abstract). MGC teaches the use of a Col8A2 gene that is 1938 base pairs long and has a complementary region comprising 100% sequence identity to the claimed SEQ ID NO: 1064 (i.e., a Col8A2 gene comprising a Gln455 Lys mutation) (see attached sequence alignment).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the guide sequence rendered obvious by Zhang in view of Courtney and MGC for a guide sequence targeting a Col8A2 gene sequence having 100% identity to the claimed SEQ ID NO: 1064, as described by Muragaki. A person of ordinary skill in the art would have recognized that Courtney identified a need in the art to target Col8A2 as it is associated with FECD. A person of ordinary skill in the art would have recognized that there are a finite number of guide RNAs that can be designed in order to target the Col8A2 gene, as described by Zhang.. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued with a reasonable expectation of success because Zhang in view of Courtney and MGC teach that guide RNAs are able to be designed in order to target and treat a multitude of different diseases.
Claim(s) 34 and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024) in view of Wieben (WO 2013/101711 A1, cited in the IDS filed 30 May 2024) as applied to claims 1, 4-5, 42-43, 50, and 84-85 above, and further in view of Jun (PG Pub No. WO 2017/004616 A1, filed 2 July 2015).
Regarding claim 80, Zhang in view of Wieben renders obvious claims 1, 4-5, 42-43, 50, and 84-85 as described above. Zhang further teaches that the system may have a Cas protein having one or more mutations and two guide RNAs that target a first strand and a second strand of a DNA molecule respectively ([0057]).
Zhang in view of Wieben does not teach or suggest the use of a second target sequence selected from the claimed SEQ ID NO: 114 (Claims 34 and 40).
However, one of ordinary skill in the art would have considered the teachings of Jun as both references are common fields of endeavor pertaining to the use of CRISPR systems in the treatment of Fuchs endothelial corneal dystrophy via the targeting of a TCF4 gene.
Jun is drawn towards an invention concerned with methods for treating disorders affecting ocular tissue (Abstract). Jun teaches the use of CRISPR guide RNAs that can target sequences in a TCF4 gene (pg. 4). Jun teaches that a sequence having 100% identity to the claimed SEQ ID NO: 114 was a known target sequence in a TCF4 gene that causes Fuchs endothelial corneal dystrophy (pg. 25; see SEQ ID NO: 213).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the second guide RNA sequence rendered obvious by Zhang in view of Wieben for a sequence having 100% identity to the claimed SEQ ID NO: 114, as described by Jun. A person of ordinary skill in the art would have been motivated to do so in order to target a known sequence that is associated with FECD. A person of ordinary skill in the art would have had a reasonable expectation of success because both Zhang in view of Wieben and Jun teach the use of CRISPR systems that can utilize guide RNAs to target TCF4 genes in order to treat FECD.
Claim(s) 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024) in view of Wieben (WO 2013/101711 A1, cited in the IDS filed 30 May 2024) as applied to claims 1, 4-5, 42-43, 50, and 84-85 above, and further in view of Brito (PG Pub No. WO 2015/095340 A1).
Regarding claim 80, Zhang in view of Wieben renders obvious claims 1, 4-5, 42-43, 50, and 84-85 as described above.
Zhang in view of Wieben does not teach or suggest the use of a lipid nanoparticle that comprises a CCD lipid (Claim 80).
However, one of ordinary skill in the art would have considered the teachings of Brito as both references are common fields of endeavor pertaining to the delivery of RNA of interest to cells.
Brito is drawn towards an invention concerned with the use of a pharmaceutical composition comprising a lipid nanoparticle (pg. 3). Brito teaches that the lipid nanoparticle can be utilized to deliver a biologically active agent, selected from RNA, to a cell of interest (pg. 4). Brito teaches that the lipid nanoparticle can comprise a helper lipid selected from cholesterol (i.e., a CCD lipid) (pg. 21-22). Brito teaches that utilizing a lipid nanoparticle to deliver RNA is advantageous because RNA is particularly difficult to deliver to cells as a bio therapeutic and utilizing a lipid nanoparticle to stabilize the RNA molecule allows for the successful delivery of the RNA to cells of interest (pg. 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Zhang in view of Wieben such that the guide RNA was delivered via a lipid nanoparticle comprising a CCD lipid, as described by Brito. A person of ordinary skill in the art would have been motivated to do so in order to stabilize the RNA molecule and allow for its delivery as a biotherapeutic to a target cell of interest. A person of ordinary skill in the art would have had a reasonable expectation of success because both Zhang in view of Wieben and Brito are drawn towards the delivery of RNA molecules to a cell of interest.
Claim(s) 83 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2014/0357530 A1, cited in the IDS filed 30 May 2024), Courtney (Int J Ophthalmol Eye Res. S 2 (2015): 7-18), and Mammalian Genome Collection (i.e., MGC) (Proceedings of the National Academy of Sciences 99.26 (2002): 16899-16903) as applied to claims 23, 25, 33, 81-82, and 86-88 above, and further in view of Brito (PG Pub No. WO 2015/095340 A1).
Regarding claim 83, Zhang in view of Courtney and MGC renders obvious claims 23, 25, 33, 81-82, and 86-88 as described above.
Zhang in view of Courtney and MGC does not teach or suggest the use of a lipid nanoparticle that comprises a CCD lipid (Claim 83).
However, one of ordinary skill in the art would have considered the teachings of Brito as both references are common fields of endeavor pertaining to the delivery of RNA of interest to cells.
Brito is drawn towards an invention concerned with the use of a pharmaceutical composition comprising a lipid nanoparticle (pg. 3). Brito teaches that the lipid nanoparticle can be utilized to deliver a biologically active agent, selected from RNA, to a cell of interest (pg. 4). Brito teaches that the lipid nanoparticle can comprise a helper lipid selected from cholesterol (i.e., a CCD lipid) (pg. 21-22). Brito teaches that utilizing a lipid nanoparticle to deliver RNA is advantageous because RNA is particularly difficult to deliver to cells as a bio therapeutic and utilizing a lipid nanoparticle to stabilize the RNA molecule allows for the successful delivery of the RNA to cells of interest (pg. 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Zhang in view of Courtney and MGC such that the guide RNA was delivered via a lipid nanoparticle comprising a CCD lipid, as described by Brito. A person of ordinary skill in the art would have been motivated to do so in order to stabilize the RNA molecule and allow for its delivery as a biotherapeutic to a target cell of interest. A person of ordinary skill in the art would have had a reasonable expectation of success because both Brito and Zhang in view of Wi in view of Courtney and MGC are drawn towards the delivery of RNA molecules to a cell of interest.
Response to Arguments
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Applicant alleges that no prima facie case of obvious has been made utilizing Zhang and Wieben because there was no motivation to make a guide sequence required by the present claims and there was no reasonable expectation that one could have done so successfully. This argument is not found persuasive because MPEP 2143(I)(E) teaches that utilizing the “obvious to try” rationale requires the following:
“(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.”
In the instant case, Zhang teaches that (1) there was a need in the art to target genes associated with FECD by targeting an S. pyogenes CRISPR system to a defect in a target sequence that is upstream of a NGG PAM sequence, (2) that the TCF4 gene of Wieben was of finite length and upstream of an AGG sequence (i.e., an NGG PAM sequence) while Zhang teaches that guide RNAs that are 20 nucleotides in length could be designed to target a TCF4 gene, and (3) the known potential solutions could have been pursued with a reasonable expectation of success because Zhang teaches that guide RNAs are able to be designed and their targeting ability tested in order to target and treat a multitude of different diseases. Thus, as required by MPEP 2143(I)(E), Zhang in view of Wieben renders obvious the claimed pharmaceutical formulation.
Applicant alleges that Zhang provides a very large genus of diseases, including FECD, but provides no evidence that one can successfully target the associated TCF4 gene to treat the disease.
This argument is not found persuasive because the large list of possible diseases in Zhang that could be targeted with guide RNAs is further evidence that the CRISPR system of Zhang is so well known and routine that a multitude of different diseases could be treated by the system via the targeting of genes associated with the diseases. As Wieben further teaches, the TCF4 gene is a gene that is known to be associated with FECD. Thus, a person of ordinary skill in the art would have recognized that Zhang in view of Wieben renders obvious the claimed composition.
Applicant alleges that the claimed SEQ ID NOs: 85 and 1173 are sequences that merely exist within a gene (i.e., the TCF4 gene of Wieben), and nothing in the cited art provides motivation to target the specifically claimed SEQ ID NOs: 85 or 1173.
This argument is not found persuasive because, as discussed above, Zhang teaches that an S. pyogenes CRISPR system can be targeted to a defect in a target sequence that is upstream of a NGG PAM sequence while the target sequences of Wieben were of finite length and upstream of an AGG sequence (i.e., an NGG PAM sequence). Thus, it would have been obvious to one of ordinary skill in the art to try to target the sequences of Wieben with the CRISPR system of Zhang, as discussed above. Further, MPEP 2143(I)(E) does not require an explicit motivation in order to render a particular invention obvious.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636